Suppression of viral RNA polymerase activity is necessary for persistent infection during the transformation of measles virus into SSPE virus

Author summarySubacute sclerosing panencephalitis (SSPE) is a rare but fatal disease in apparently healthy children, which develops 7 to 10 years after acute measles. Measles virus (MV) persistently infects the brain, accumulates mutations, and transforms into neuropathogenic SSPE virus. The World Health Organization is promoting vaccination against MV to achieve global eradication of measles; this is also the most effective approach for prevention of SSPE. The live MV vaccine strains do not cause SSPE and all SSPE viruses isolated thus far have been derived from wild-type MV strains, but it remains unclear why live MV vaccine strains do not cause SSPE. Recently hyperfusogenic mutations of the MV F protein were proved to account for the enhanced propagation of the virus in the brain leading to the neurovirulence. In this study we showed that suppression of viral RNA polymerase is implicated in the establishment of persistent wild-type MV infection within neurons. Further investigations of the mechanisms by which wild-type MV transforms into SSPE virus will shed light on the reason why MV vaccine strains do not acquire neurovirulence. Subacute sclerosing panencephalitis (SSPE) is a fatal neurodegenerative disease caused by measles virus (MV), which typically develops 7 to 10 years after acute measles. During the incubation period, MV establishes a persistent infection in the brain and accumulates mutations that generate neuropathogenic SSPE virus. The neuropathogenicity is closely associated with enhanced propagation mediated by cell-to-cell fusion in the brain, which is principally regulated by hyperfusogenic mutations of the viral F protein. The molecular mechanisms underlying establishment and maintenance of persistent infection are unclear because it is impractical to isolate viruses before the appearance of clinical signs. In this study, we found that the L and P proteins, components of viral RNA-dependent RNA polymerase (RdRp), of an SSPE virus Kobe-1 strain did not promote but rather attenuated viral neuropathogenicity. Viral RdRp activity corresponded to F protein expression; the suppression of RdRp activity in the Kobe-1 strain because of mutations in the L and P proteins led to restriction of the F protein level, thereby reducing cell-to-cell fusion mediated propagation in neuronal cells and decreasing neuropathogenicity. Therefore, the L and P proteins of Kobe-1 did not contribute to progression of SSPE. Three mutations in the L protein strongly suppressed RdRp activity. Recombinant MV harboring the three mutations limited viral spread in neuronal cells while preventing the release of infectious progeny particles; these changes could support persistent infection by enabling host immune escape and preventing host cell lysis. Therefore, the suppression of RdRp activity is necessary for the persistent infection of the parental MV on the way to transform into Kobe-1 SSPE virus. Because mutations in the genome of an SSPE virus reflect the process of SSPE development, mutation analysis will provide insight into the mechanisms underlying persistent infection.